Biomedical subjects

Jason L Hornick

Publications and source records attributed to Jason L Hornick.

At least 19 recordsLinked to original sources

PubMed2007

Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis.

PURPOSE: The distribution and significance of caveolin 1 (CAV1) expression in different breast cell types and role in breast carcinogenesis remain poorly understood. Both tumor-suppressive and oncogenic roles have been proposed for this protein. The aims of this study were to characterize the distribution of CAV1 in normal breast, benign breast lesions, breast cancer precursors, and metaplastic breast carcinomas; to assess the prognostic significance of CAV1 expression in invasive breast carcinomas; and to define whether CAV1 gene amplification is the underlying genetic mechanism driving CAV1 overexpression in breast carcinomas. EXPERIMENTAL DESIGN: CAV1 distribution in frozen and paraffin-embedded whole tissue sections of normal breast was evaluated using immunohistochemistry, immunofluorescence, and immunoelectron microscopy. CAV1 expression was immunohistochemically analyzed in benign lesions, breast cancer precursors, and metaplastic breast carcinomas and in a cohort of 245 invasive breast carcinomas from patients treated with surgery followed by anthracycline-based chemotherapy. In 25 cases, CAV1 gene amplification was assessed by chromogenic in situ hybridization. RESULTS: In normal breast, CAV1 was expressed in myoepithelial cells, endothelial cells, and a subset of fibroblasts. Luminal epithelial cells showed negligible staining. CAV1 was expressed in 90% of 39 metaplastic breast carcinomas and in 9.4% of 245 invasive breast cancers. In the later cohort, CAV1 expression was significantly associated with 'basal-like' immunophenotype and with shorter disease-free and overall survival on univariate analysis. CAV1 gene amplification was found in 13% of cases with strong CAV1 expression. CONCLUSIONS: The concurrent CAV1 amplification and overexpression call into question its tumor-suppressive effects in basal-like breast carcinomas.

Breast↗

PubMed2006

The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans.

Histiocytic sarcoma (HS) is a rare malignant proliferation of histiocytes of uncertain molecular pathogenesis. Here, genetic analysis of coincident loss of Pten and Ink4a/Arf tumor suppressors in the mouse revealed a neoplastic phenotype dominated by a premalignant expansion of biphenotypic myelolymphoid cells followed by the development of HS. Pten protein loss occurred only in the histiocytic portion of tumors, suggesting a stepwise genetic inactivation in the generation of HS. Similarly, human HS showed genetic or epigenetic inactivation of PTEN, p16(INK4A), and p14(ARF), supporting the relevance of this genetically engineered mouse model of HS. These genetic and translational observations establish a cooperative role of Pten and Ink4a/Arf in the development of HS and provide mechanistic insights into the pathogenesis of human HS.

Animals↗

PubMed2006

Prevalence and significance of prominent mucin pools in the esophagus post neoadjuvant chemoradiotherapy for Barrett's-associated adenocarcinoma.

Occasionally, patients with Barrett's-associated adenocarcinoma who received preoperative chemoradiotherapy (chemrad) show prominent mucin pools in their resection specimen, but the prognostic significance of this finding has never been investigated. The purpose of this study was to evaluate the clinical and pathologic features, and prognostic significance, of prominent mucin pools in 21 patients identified from a cohort of 192 consecutive cancer patients (prevalence rate, 10.9%) who had an esophagectomy (post-chemrad) for adenocarcinoma. The clinical and pathologic features and follow-up data were evaluated in 21 patients with adenocarcinoma of the esophagus and with prominent mucin pools (male-to-female ratio, 21:0; mean age, 61 years) and compared with a control group of 19 consecutive chemrad-treated and stage-matched esophageal adenocarcinoma patients who had either minimal microscopic (9 cases) or no (10 cases), residual disease present in their resection specimen (male-to-female ratio, 18:1; mean age, 62 years). Of the 21 study patients, 7 (33%) had acellular mucin pools with no residual tumor, 7 (33%) showed rare isolated tumor cells within mucin pools, and 7 (33%) had acellular mucin pools with microscopic foci of residual adenocarcinoma in tissue adjacent to, but not within, mucin pools. In total, 2 cases (9%) showed mucin pools limited to the submucosa, 5 (24%) showed involvement of the muscularis propria, and 14 (67%) showed mucin pools within the muscularis propria and adventitia. Four cases (19%) showed involvement of the radial resection margin with acellular mucin pools. Thirteen study patients (62%) contained acellular mucin pools within regional lymph nodes. A significantly higher proportion of patients with prominent mucin pools had mucinous adenocarcinoma prior to neoadjuvant therapy, compared with control patients without mucin pools (12 of 21 (57%) vs. 1 of 19 (5%), P < 0.001). Upon follow-up (mean, 27 months; range, 5-84 months), none of the study patients with prominent mucin pools died of disease (0%), in comparison to 5 of 19 (26%) control patients (mean follow-up, 27 months; range, 3-64 months) (P = 0.02). None of the patients who had acellular mucin pools involving the radial margin developed recurrence or metastasis or died of disease. Prominent mucin pools in resection specimens from patients with Barrett's esophagus-associated adenocarcinoma who received preoperative chemrad are associated with mucinous tumors and are not associated with poor survival, even when acellular mucin pools involve the radial margin, and, thus, should not be interpreted as evidence of residual viable adenocarcinoma.

Adenocarcinoma↗

PubMed2006

Intraarticular nodular fasciitis--a rare lesion: clinicopathologic analysis of a series.

Nodular fasciitis is a benign myofibroblastic proliferation with a predilection for the subcutaneous tissues of the upper extremities, trunk, and head and neck of young adults. Nodular fasciitis is not generally recognized to arise within joints. In this study, the clinicopathologic and immunohistochemical features of 10 cases of intraarticular nodular fasciitis are described. Six patients were female and 4 were male, with a median age of 33 years (range, 9-50 years). Lesional size ranged from 2 to 4 cm (median, 2.6 cm). Seven tumors arose in the knee, 2 in the hand, and 1 in the ankle. Most patients complained of joint pain; 4 presented with a palpable mass. Only 1 patient reported antecedent trauma. The duration of symptoms prior to surgery ranged from 2 months to 1 year (median, 6 months). The clinical differential diagnoses included giant cell tumor of tendon sheath, pigmented villonodular synovitis, synovial chondromatosis, inflammatory arthritis, and lymphoma. Grossly, the lesions were solid, nodular, rubbery, or firm masses. Histologically, all tumors were circumscribed but unencapsulated and showed typical features of nodular fasciitis, being composed of cytologically bland plump spindle cells arranged in short, intersecting bundles within a variably loose myxoid to collagenous stroma, containing extravasated red blood cells and scattered lymphocytes. Five lesions showed prominent stromal hyalinization, in 2 cases keloidal in appearance. In 4 cases, the tissue at the periphery of the lesion showed hemosiderin deposition. By immunohistochemistry, all tumors examined were positive for SMA, 1 was positive for desmin, and all were negative for caldesmon and S-100 protein; none showed nuclear staining for beta-catenin. Clinical follow-up information was available for 5 patients, ranging from 2 to 86 months. No lesion recurred. In summary, intraarticular nodular fasciitis occurs most commonly in the knees of young adults, and often appears to have a somewhat longer preoperative duration than typical subcutaneous or intramuscular nodular fasciitis. Intraarticular lesions show morphologic features similar to other cases of nodular fasciitis, with the exception that stromal hyalinization and adjacent hemosiderin deposition are common, likely attributable to frictional trauma in this location.

Adolescent↗

PubMed2006

Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases.

Spindle cell (sarcomatoid) carcinoma of the breast is a rare variant of breast cancer that has been classified under the broad rubric of metaplastic carcinoma. Because the term "metaplastic carcinoma" comprises a heterogeneous group of tumors, it has been difficult to reliably predict biologic potential or to determine optimal therapy. To better characterize the spindle cell subset of metaplastic breast carcinomas, we reviewed 29 cases. All patients were adult females ranging from 40 to 96 years of age (median, 68 years). Tumor size ranged from 1.5 to 15 cm (median, 4 cm). Treatment was by excision and/or mastectomy with axillary node evaluation in most cases, often combined with postoperative radiation and/or chemotherapy. All cases were clinically of breast origin, showed >or=80% spindled/sarcomatoid morphology, and demonstrated keratin positivity and/or close association with ductal carcinoma in situ. Immunohistochemical studies showed evidence suggesting myoepithelial differentiation as exhibited by immunoreactivity for smooth muscle actin, cytokeratin 14, and p63 in a subset of cases (39%). Twenty-seven cases exhibited pure spindled or sarcomatoid morphology of variable appearance and nuclear grade, whereas 2 contained high-grade invasive ductal carcinoma comprising <or=20% of the tumor mass. Two cases exhibited heterologous elements (1 rhabdomyosarcoma and 1 with both chondrosarcoma and osteosarcoma) and 4 were associated with ductal carcinoma in situ. Follow-up data were available on 24 of 29 patients (range, 1-120 months; median, 20 months). Of 20 cases in which axillary nodes were biopsied, definitive nodal metastases were identified in only 1 (5%), and this was in a case with a significant component of invasive ductal carcinoma. Three patients developed local recurrences. Extranodal metastases occurred in 11 of 24 patients (46%), most commonly to the lungs. Ten of 24 patients (42%) died of disease at a median interval of 11.5 months (range, 1-46 months) and 3 patients were alive with metastatic disease. Eight patients were alive with no evidence of recurrent or metastatic disease (median, 29.5 months). Based on this series, spindle cell/sarcomatoid carcinoma of the breast is a highly aggressive neoplasm with a high rate of extranodal metastases. Purely spindled/sarcomatoid tumors have a significantly lower rate of nodal metastases than conventional ductal and lobular breast carcinomas.

Adult↗

PubMed2006

Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG.

The homeodomain transcription factor, NANOG, along with OCT3/4 (POU5F1) and SOX2, is part of the core set of transcription factors that maintain embryonic stem cell self-renewal and pluripotency. Expression of NANOG has been detected in fetal germ cells and in gonadal germ cell tumors. To assess the diagnostic utility of NANOG in central nervous system (CNS) germ cell tumors, we analyzed its expression by immunohistochemistry in a series of 12 CNS germinomas and compared its expression with other stem cell markers. Strong nuclear expression of NANOG was demonstrated in >90% of the tumor cells in all cases. In contrast, expression of OCT3/4 and placental alkaline phosphatase was inconsistent and SOX2 was expressed in only rare cells. NANOG was not detected in tumor types frequently considered in the differential diagnosis of CNS germinoma: pineoblastoma, primitive neuroectodermal tumors, medulloblastoma, lymphoma, pituitary adenoma, atypical teratoid/rhabdoid tumor, Langerhans cell histiocytosis, and gliomas. These findings demonstrate that NANOG is a sensitive and specific marker of CNS germinoma. Compared with other currently used markers, NANOG may have superior diagnostic characteristics and can facilitate identification of germinomas in minute surgical biopsies commonly obtained from these tumors. These findings also suggest a potential biologic role for NANOG in maintenance of CNS germinoma.

Adolescent↗

PubMed2006

Immunohistochemical staining for claudin-1 can help distinguish meningiomas from histologic mimics.

The histologic distinction between meningiomas and other tumors of the central nervous system occasionally can be difficult. Claudin-1 is a tight junction-associated protein recently shown to be expressed in anaplastic meningiomas. The purpose of this study was to determine whether immunohistochemical staining for claudin-1 could help distinguish meningiomas from histologic mimics, compared with commonly used markers. Tissue sections from 10 meningothelial meningiomas, 20 fibrous meningiomas, 10 atypical meningiomas, 7 solitary fibrous tumors of the meninges, 5 meningeal hemangiopericytomas, and 7 vestibular schwannomas were stained immunohistochemically for claudin-1, epithelial membrane antigen, S-100 protein, CD34, and glial fibrillary acidic protein. In total, 21 (53%) of 40 meningiomas were immunoreactive for claudin-1, whereas none of the other tumors were positive. In contrast, there was considerable overlap in the distribution of the other antibodies evaluated. Claudin-1 seems to be a specific marker for meningiomas in this context. Although its sensitivity is relatively low, claudin-1 may be helpful in a panel of immunostains to distinguish meningiomas from histologic mimics.

Antigens, CD34↗

PubMed2005

Intraabdominal cystic lymphangiomas obscured by marked superimposed reactive changes: clinicopathological analysis of a series.

Cystic (or cavernous) lymphangiomas are uncommon tumors that most often occur in the head and neck, axilla, or groin of young children but are detected occasionally in adulthood at various other anatomic sites. When arising in the abdomen, cystic lymphangiomas may present with acute abdominal pain. We have encountered examples of mesenteric and retroperitoneal cystic lymphangiomas associated with such marked superimposed reactive and inflammatory changes that their lymphatic nature is obscured, a situation that is not widely recognized. To further characterize these lesions, 7 abdominal lymphangiomas associated with florid reactive changes were retrieved from the authors' consultation files. There were 5 female patients and 2 male patients (median age, 42 years; range, 1 month to 51 years). Five cases presented in adulthood. Tumor size ranged from 8 to 20 cm (median, 15 cm). Three tumors arose in the mesentery of the small intestine and 4 arose in the retroperitoneum (one of which also involved the posterior mediastinum). Three patients presented with a short history of abdominal pain. Radiological studies revealed large cystic or solid masses; clinical differential diagnoses included sarcoma (2 cases), enteric duplication cyst (2 cases), and cystic tumor not otherwise specified. Grossly, the tumors were generally multiloculated cystic masses associated with areas of fat necrosis and hemorrhage. The cysts often contained thick, gelatinous, or milky fluid. Histologically, all cases showed extensive areas of granulation tissue, most also including a floridly cellular reactive myofibroblastic proliferation, obscuring the lymphatic nature of the lesion. Two cases contained extensive areas of xanthogranulomatous inflammation. In foci where the underlying lesion could be discerned, the tumors were composed of cystically dilated lymphatic spaces, some of which were partially invested by a layer of smooth muscle and were associated with occasional lymphoid aggregates. The lymphatic spaces contained either clear fluid or large numbers of foamy macrophages. The lymphatic endothelial cells lining the cystic spaces were generally attenuated with no cytological atypia. One case showed features of a complex vascular malformation with a predominant component of cavernous lymphangioma. By immunohistochemistry, in all cases, the endothelial cells lining the dilated lymphatic spaces were positive for CD31 and D2-40, 4 of 7 were positive for CD34, and all were negative for keratin. Clinical follow-up information was available for 4 patients (median, 26 months; range, 22-36 months): 3 patients had no evidence of recurrence and 1 patient was asymptomatic with radiographic evidence of minimal persistent disease. In summary, some intraabdominal lymphangiomas have a tendency to induce marked reactive and inflammatory changes in the surrounding tissues, often obscuring their nature and occasionally leading to the clinical impression of a malignant tumor. Awareness of this unusual occurrence will lead to the correct diagnosis.

Abdominal Neoplasms↗

PubMed2005

Biologic properties of columnar epithelium underneath reepithelialized squamous mucosa in Barrett's esophagus.

Chronic proton pump inhibitor (PPI) therapy may lead to partial regression of Barrett's esophagus (BE), resulting in the development of reepithelialized islands of squamous mucosa that may cover the underlying BE. The purpose of this study was to evaluate the clinical, histologic, and biologic characteristics of BE that is situated underneath squamous islands (BUSI). A total of 97 mucosal biopsies from 44 BE patients with BUSI were evaluated for a variety of histologic features (eg, type of epithelium, anatomic relationship of the underlying glands to the luminal surface, presence of adjacent mucosal glands or ducts, and the presence and degree of dysplasia), and immunostained for Ki-67, cyclin D1, and p53. BUSI was compared with adjacent areas of BE for all parameters. A clinical control group consisting of 50 BE patients without microscopic evidence of BUSI was selected for comparison of clinical and endoscopic features. The study group (34 males, 10 females; mean age, 67 years; mean length of BE, 5.5 cm) consisted of 27 (61%) and 12 (27%) patients on low- and high-dose PPI, respectively. On endoscopy, visible islands of squamous mucosa were noted in only 43% of study group patients (despite the presence of BUSI microscopically in all cases); one island was noted in 2%, multiple islands in 27%, and extensive islands in 14% of patients. The extent of squamous islands was unrelated to PPI dose. The study group was significantly more likely to have endoscopic evidence of extensive squamous islands compared with the control group (P = 0.009). Histologically, 89% of biopsies with BUSI showed intestinal-type, and 11% showed cardia-type, epithelium. Low- and high-grade dysplasia was noted in 4 (4%) and 5 (5%) biopsies, respectively. All patients with dysplasia in BUSI also showed dysplasia in other areas of the esophagus as well. Interestingly, BUSI reached the mucosal surface either by penetrating directly through, or by wrapping around, islands of squamous epithelium, in 68% of biopsies. Twenty-one percent of biopsies showed BUSI adjacent to submucosal glands or ducts. BUSI showed a significantly lower Ki-67 proliferation rate (29% vs. 49%, P < 0.001), and a lower, albeit nonsignificant, degree of cyclin D1 (16% vs. 29%) and p53 (4% vs. 17%) positivity in comparison to adjacent areas of BE. Furthermore, significantly lower proliferation rates were observed in BUSI that did not reveal an opening to the mucosal surface in comparison to foci that did. BUSI is phenotypically similar to typical surface BE but shows less severe proliferative abnormalities, particularly in buried glands that have no detectable connection to the esophageal lumen. Reduced proliferation may be due either to decreased exposure to luminal contents or to disruption of sloughing of surface epithelial cells into the crypt lumen. Prospective studies of large numbers of patients with BUSI will be required to determine the magnitude of its risk of progression to cancer.

Aged↗

PubMed2005

Immunohistochemistry can help distinguish metastatic pancreatic adenocarcinomas from bile duct adenomas and hamartomas of the liver.

Not uncommonly, bile duct adenomas (BDAs) and hamartomas (BDHs) of the liver may be difficult to distinguish from metastatic well-differentiated ductal adenocarcinoma of the pancreas. However, this distinction is critical for proper staging and patient management. The primary purpose of this study was to determine if a panel of immunohistochemical stains can help distinguish BDA or BDH from metastatic pancreatic adenocarcinoma in the liver. Routinely processed tissue sections from 25 BDA, 10 BDH, 25 metastatic pancreatic adenocarcinomas to the liver and 6 cases each of metastatic colorectal, breast, and lung adenocarcinomas were immunohistochemically stained for CK7, CK8/CK18, CK19, CK20, p53, p63, TAG-72, monoclonal CEA (mCEA), polyclonal CEA (pCEA), HER-2/neu, AMACR (alpha-methylacyl-CoA racemase), Dpc4 (Smad4), and mesothelin. The slides were evaluated in a blinded fashion, and the results were compared between the benign and malignant lesions. Significantly more (P < 0.05) metastatic pancreatic adenocarcinomas were positive for CK20 (76%), p53 (60%), TAG-72 (88%), mCEA (92%), HER2/neu (40%), and mesothelin (64%) and showed loss of Dpc4 (44%), in comparison to BDA (CK20, 40%; p53, 0%; TAG-72, 0%; mCEA, 0%; HER2/neu, 12%; mesothelin, 0%; loss of Dpc4, 0%) or BDH (CK20, 10%; p53, 0%; TAG-72, 0%; mCEA, 10%; HER2/neu, 0%; mesothelin, 0%; loss of Dpc4, 0%). Of these antibodies, p53, TAG-72, mCEA, loss of Dpc4, and mesothelin had the highest specificity for pancreatic adenocarcinoma, with mCEA having the highest sensitivity (92%). No significant differences were observed in the degree of CK7, CK8/CK18, CK19, or pCEA expression between the three types of lesions. Although none of the BDA or BDH was positive for either p63 or AMACR, two of the metastatic pancreatic adenocarcinomas (8%) were positive for each of these peptides (P > 0.05). For nonpancreatic adenocarcinomas, mCEA showed a reasonably high sensitivity and 100% specificity in the differential diagnosis versus BDA. Immunohistochemical expression of p53, TAG-72, mCEA, mesothelin, and loss of Dpc4 can help distinguish metastatic pancreatic adenocarcinoma in the liver from BDA or BDH. Although p63 and AMACR are also specific for pancreatic adenocarcinoma, their low sensitivity limits their use in clinical practice.

Adenocarcinoma↗

PubMed2005

Intestinal perineuriomas: clinicopathologic definition of a new anatomic subset in a series of 10 cases.

Benign peripheral nerve sheath tumors are uncommon in the gastrointestinal tract, and perineuriomas have not previously been reported to occur at this anatomic location. In this study, we analyzed the clinicopathologic and immunohistochemical features of 10 perineuriomas arising in the intestine. Eight patients were female and 2 male (median age, 51 years; range, 35-72 years). Eight of the lesions were intramucosal perineuriomas presenting as small sessile polyps detected during colonoscopy; 6 of these 8 patients were asymptomatic and undergoing colorectal cancer screening. The remaining 2 cases were submucosal masses, one each located in the colon and jejunum. Of the mucosal polyps, six were located in the rectosigmoid or sigmoid colon and one each was detected in the descending colon and transverse colon. The polyps ranged from 0.2 to 0.6 cm (median, 0.4 cm) in greatest dimension. The colonic and jejunal masses measured 3 cm and 4.5 cm, respectively. Histologically, the intramucosal perineuriomas were composed of uniform bland spindle cells having ovoid to elongated nuclei and pale indistinct cytoplasm, with no cytologic atypia, pleomorphism, or mitotic activity. The lesions had a fine collagenous stroma, demonstrated irregular borders with the adjacent lamina propria, and entrapped colonic crypts. Five cases exhibited hyperplastic changes in the adjacent or entrapped epithelium. The colonic submucosal tumor was microscopically well circumscribed, whereas the jejunal perineurioma showed focal infiltration through the muscularis propria into the subserosa. The stroma was collagenous in the colonic tumor and predominantly myxoid in the jejunal tumor. The spindle cells in the submucosal perineuriomas demonstrated tapered nuclei and elongated bipolar cytoplasmic processes. All tumors except one were positive for epithelial membrane antigen (EMA); 4 of 10 expressed claudin-1 and 2 of 10 expressed CD34. All tumors were negative for S-100 protein, glial fibrillary acidic protein, neurofilament protein, smooth muscle actin, desmin, caldesmon, KIT, and pan-keratin. Electron microscopy was performed on the tumor lacking EMA expression, revealing typical features of perineurioma, namely, spindle cells with long bipolar cytoplasmic processes and prominent pinocytotic vesicles, surrounded by discontinuous basal lamina. Clinical follow-up was available for 4 patients (median, 34 months; range, 8-53 months). No tumor recurred. In summary, perineuriomas may arise in the intestine, most often as intramucosal lesions detected as colorectal polyps with distinctive histologic features including entrapment of colonic crypts. Distinguishing perineuriomas from other spindle cell neoplasms of the gastrointestinal tract can be facilitated by immunostaining for EMA and claudin-1.

Adult↗

PubMed2005

Soft tissue perineurioma: clinicopathologic analysis of 81 cases including those with atypical histologic features.

Perineuriomas are uncommon benign peripheral nerve sheath tumors that include soft tissue, sclerosing, and intraneural variants. Fewer than 50 soft tissue perineuriomas have been reported to date, and the clinical significance of atypical histologic features is unknown. To characterize these tumors further, 81 soft tissue perineuriomas received between 1994 and 2003 were retrieved from the authors' consult files. Hematoxylin and eosin sections were reexamined, immunohistochemistry was performed, and clinical details were obtained from referring physicians. Forty-three patients were female and 38 male (mean age, 46 years; range, 10-79 years). Tumor size ranged from 0.3 to 20 cm (mean, 4.1 cm) in greatest dimension. Most patients presented with a painless mass. The tumors arose in a wide anatomic distribution: 36 lower limb, 19 upper limb, 15 trunk, 7 head and neck, 3 retroperitoneum, and 1 paratesticular. Forty-two tumors were situated primarily in subcutis, 25 in deep soft tissue, and 9 were limited to the dermis. Nearly all cases were grossly well circumscribed; 12 showed focal microscopically infiltrative margins. Most tumors had a storiform and focally whorled growth pattern; 17 exhibited fascicular areas. Thirty-eight tumors were hypocellular, 15 were markedly hypercellular, and 7 showed alternating zones of hypocellularity and hypercellularity. Stroma was usually collagenous but in 17 tumors was predominantly myxoid, and in 16 was mixed collagenous and myxoid. Mitoses ranged from 0 to 13 per 30 high power fields (mean, 1); 53 tumors had no mitoses. Based on worrisome cytologic or architectural features, 14 cases were classified as atypical perineuriomas: 12 contained scattered pleomorphic cells, 1 showed an abrupt transition from typical morphology to a markedly hypercellular, fascicular area with cytologic atypia, and 1 exhibited diffuse infiltration of skeletal muscle. All tumors were reactive for epithelial membrane antigen; 50 of 78 (64%) expressed CD34, 22 of 76 (29%) claudin-1, 16 of 77 (21%) smooth muscle actin, and 4 of 81 (5%) S-100 protein. All tumors were negative for glial fibrillary acidic protein, neurofilament protein, and desmin. Clinical follow-up was available for 43 patients (mean, 41 months; range, 6-146 months). Among tumors for which the status of surgical margins was known, 52% were widely excised, 31% were marginally excised, and 18% had positive margins. Only two tumors recurred locally (one of which was atypical): one recurred 10 years following primary excision; and one recurred twice, 5 and 9 years following excision. No tumor metastasized. Soft tissue perineuriomas behave in a benign fashion and rarely recur. Atypical histologic features (including scattered pleomorphic cells and infiltrative margins) seem to have no clinical significance and appear to be akin to those seen in ancient schwannoma and atypical (bizarre) neurofibroma.

Adolescent↗

PubMed2004

Protein Kinase C theta (PKCtheta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs).

KIT expression is a key diagnostic feature of gastrointestinal stromal tumors (GISTs), and virtually all of the GISTs express oncogenic forms of the KIT or PDGFRA receptor tyrosine kinase proteins, which serve as therapeutic targets of imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). However, KIT expression can be low in PDGFRA-mutant GISTs, increasing the likelihood of misdiagnosis as other types of sarcoma. We report that the signaling intermediate protein kinase C theta (PKCtheta) is a diagnostic marker in GISTs, including those that lack KIT expression and/or contain PDGFRA mutations. PKCtheta is strongly activated in most GISTs and hence may serve, along with KIT/PDGFRA, as a novel therapeutic target.

Enzyme Activation↗

PubMed2004

Cutaneous myoepithelioma: a clinicopathologic and immunohistochemical study of 14 cases.

Analogous to mixed tumors of salivary glands (" pleomorphic adenomas" ), cutaneous mixed tumors (" chondroid syringomas" ) contain a ductal (epithelial) component and a variably prominent myoepithelial component. Tumors showing purely myoepithelial differentiation (myoepitheliomas) have only recently been recognized to arise in the dermis, and to date very few cases have been described. To characterize these tumors further, 14 cutaneous myoepithelial tumors were retrieved from the authors' consult files. Eleven patients were male and 3 were female; their median age was 22.5 years (range, 10 to 63 years), and 7 patients were between 10 and 20 years old. Tumor size ranged from 0.5 to 2.5 cm (mean, 1.1 cm). Most tumors arose on the extremities: 6 on the upper limbs, 6 on the lower limbs, and 1 each on the back and nose. Ten tumors were limited to the dermis, and 5 also extended into superficial subcutis. Thirteen tumors were myoepitheliomas (lacking ductal differentiation), and 1 tumor was a myoepithelial carcinoma (exhibiting severe cytological atypia and a high mitotic rate). Histologically, 7 tumors were solid, composed of ovoid to spindled, histiocytoid, or epithelioid cells with no significant stroma, and 7 were predominantly lobulated, with cords or nests of epithelioid, plasmacytoid, or spindled cells with a variably reticular architecture and a chondromyxoid or collagenous/hyalinized stroma. One tumor was composed solely of plasmacytoid (hyaline) cells, and 1 exhibited extensive adipocytic differentiation. Among the 13 myoepitheliomas, mitoses ranged from 0 to 6 per 10 high-power fields (HPFs) (mean, 1.5); 8 tumors contained no mitoses. The myoepithelial carcinoma had 39 mitoses per 10 HPFs. By immunohistochemistry, all cases were reactive for epithelial markers (keratins and/or epithelial membrane antigen [EMA]); 13 of 14 (93%) expressed S-100 protein, 10 of 11 expressed (91%) calponin, 11 of 14 (79%) expressed EMA, 9 of 14 (64%) expressed keratins, 8 of 14 (57%) expressed smooth muscle actin, 7 of 14 (50%) expressed glial fibrillary acidic protein, 3 of 11 (27%) expressed p63, and 1 of 6 (17%) expressed desmin. All 5 cases without keratin staining were diffusely positive for EMA, and all of these cases showed a solid growth pattern. Follow-up was available for 8 patients (median follow-up, 40 months; range, 6 months to 9 years); 3 tumors (38%) recurred locally, and 1 tumor (13%) also metastasized to the lymph nodes. The case that resulted in recurrence and metastasis had the highest mitotic rate (6 per 10 HPFs) of the cytologically benign tumors. Follow-up information was not available for the myoepithelial carcinoma. This study suggests that approximately 50% of cutaneous myoepitheliomas are distinctive lesions composed of a solid proliferation of cells with abundant eosinophilic syncytial cytoplasm, which often lack immunostaining for keratin, whereas the remainder demonstrate focally reticular architecture and myxoid stroma or plasmacytoid cells, similar to their counterparts in salivary gland and soft tissue. Whereas most cutaneous myoepitheliomas behave in a benign fashion, there is apparently a significant risk for local recurrence but a low metastatic potential.

Adolescent↗

PubMed2004

Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis.

BACKGROUND & AIMS: A previously published study by our group suggested that adenoma-like dysplasia-associated lesions or masses (DALMs) in ulcerative colitis (UC) may be treated adequately by polypectomy and continued endoscopic surveillance. The length of follow-up evaluation in these patients averaged only 42 months. The purpose of this study was to evaluate the long-term outcome of our previously defined group of UC patients, all with adenoma-like DALMs, who were treated by polypectomy. METHODS: The clinical, endoscopic, and pathologic outcome of 34 UC patients, 24 with an adenoma-like DALM, and 10 with a coincidental sporadic adenoma, 28 of whom were treated by polypectomy and continued endoscopic surveillance, and 6 by colonic resection, were compared with the outcome of 49 non-UC patients who were treated similarly for a sporadic adenoma. The mean length of follow-up evaluation averaged 82.1 months and 71.8 months for the 2 UC subgroups, respectively, and 60.4 months for the non-UC controls. RESULTS: Overall, 20 of 34 UC patients (58.8%) developed at least one further adenoma-like DALM on follow-up evaluation. One patient had flat low-grade dysplasia present in the colon, which was resected within 6 months of the initial polypectomy, and another patient, with primary sclerosing cholangitis, developed adenocarcinoma 7.5 years after her initial polypectomy. There was no significant difference in the prevalence of polyp formation on follow-up evaluation between UC patients with an adenoma-like DALM (62.5%) and UC patients with a sporadic adenoma (50%), or between either of these 2 UC patient subgroups and the non-UC sporadic adenoma patient group (49%; P > 0.05). CONCLUSIONS: UC patients who develop an adenoma-like DALM may be treated adequately by polypectomy with complete excision and continued endoscopic surveillance.

Adenoma↗

PubMed2004

KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications.

The diagnosis of gastrointestinal stromal tumor (GIST) is currently based on morphologic features and immunohistochemical demonstration of KIT (CD117). However, some tumors (in our estimation approximately 4%) have clinicopathologic features of GIST but do not express KIT. To determine if these lesions are truly GISTs, we evaluated 25 tumors with clinical and histologic features typical of GIST, but with negative KIT immunohistochemistry, for KIT and PDGFRA mutations using DNA extracted from paraffin-embedded tissue. Most tumors originated in the stomach (N = 14) or omentum/mesentery (N = 5). The neoplasms were composed of epithelioid cells (13 cases), admixed epithelioid and spindle cells (8 cases), or spindle cells (4 cases). Absence of KIT expression was confirmed by immunoblotting in 5 cases. Tumor karyotypes performed in 4 cases were noncomplex with monosomy 14 or 14q deletion, typical of GIST. Mutational analysis revealed PDGFRA and KIT mutations in 18 and 4 tumors, respectively, whereas 3 tumors did not have apparent KIT or PDGFRA mutations. The PDGFRA mutations primarily involved exon 18 (N = 15) and included 11 tumors with missense mutation in codon 842 (PDGFRA D842V or D842Y). In conclusion, a small subset of GISTs with otherwise typical clinicopathologic and cytogenetic features do not express detectable KIT protein. When compared with KIT-positive GISTs, these KIT-negative GISTs are more likely to have epithelioid cell morphology, contain PDGFRA oncogenic mutations, and arise in the omentum/peritoneal surface. Notably, some KIT-negative GISTs contain imatinib-sensitive KIT or PDGFRA mutations; therefore, patients with KIT-negative GISTs should not, a priori, be denied imatinib therapy.

Adult↗

PubMed2004

The clinical significance of right-sided colonic inflammation in patients with left-sided chronic ulcerative colitis.

BACKGROUND: Rarely, patchy right colonic inflammation has been observed in patients with left sided chronic ulcerative colitis (CUC), but the clinical significance of this finding is unknown. Therefore, the aim of this study was to evaluate the clinical and pathologic features and natural history of CUC patients with left-sided colitis combined with patchy right colonic inflammation and to compare the clinical course to a control group of patients with isolated left-sided CUC. METHODS: Twelve patients with clinically and pathologically confirmed left-sided CUC, but also with patchy right colonic inflammation, were identified from a cohort of 352 consecutive patients with CUC who underwent colonoscopy at the Brigham and Women's Hospital between 1996 and 2000. In this cohort, 127 patients had left-sided colitis. As the first study to use controls in this setting, 35 consecutive patients with left-sided CUC, but without patchy right colonic inflammation, were selected and evaluated during the same time period. In all patients, the medical records were reviewed for a wide variety of clinical, endoscopic, and pathologic features. The mean follow-up time for the study and control groups was 105 +/- 128 and 112 +/- 80 months, respectively. RESULTS: Patients in the study group were significantly older than the control group at the time of diagnosis (47 +/- 17 years vs 35 +/- 14 years, p = 0.048), but the two groups had a similar gender distribution (25% male vs 40% male), prevalence of extraintestinal manifestations (25% vs 11%), frequency of nonsteroidal anti-inflammatory drug use (75% vs 50%), family history of colitis (27% vs 15%), current tobacco use (8% vs 3%), history of appendectomy (8% vs 0%), and overall severity of disease (33% vs 46%). None of the patients in the study group, and only one control patient, had disease progression to pancolitis. One study patient developed high-grade dysplasia in the rectum that required a colectomy. None of the study or control patients developed clinical or pathologic features of Crohn's disease. CONCLUSIONS: Rarely patients with left-sided CUC may have patchy right colonic inflammation. The clinical features and natural history of patients with left-sided CUC and patchy right colonic inflammation is similar to patients with isolated left-sided CUC.

Adult↗

PubMed2004

Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid malignancy.

Histiocytic sarcoma is a rare malignant neoplasm that occurs in lymph nodes, skin, and the gastrointestinal tract. Many previously published cases were likely misdiagnosed examples of non-Hodgkin lymphoma. Only small numbers of bona fide examples exist in the world literature; cases arising primarily at extranodal sites are not well described and often seem to go unrecognized. To characterize these tumors further, 14 extranodal histiocytic sarcomas were analyzed. Hematoxylin and eosin sections were reexamined, immunohistochemistry was performed, and clinical details were obtained from referring hospitals. Eight patients were female and 6 male (median age, 55 years; range, 15-89 years). All patients presented with a solitary mass, ranging in size from 1.8 to 12 cm (median 6.8 cm). Seven tumors arose in soft tissue (6 lower limb; 1 upper limb), 5 in the gastrointestinal tract (1 involving both stomach and colon, 1 ileum, 2 rectum, 1 anus), 1 in the nasal cavity, and 1 in the lung. Three gastrointestinal tract tumors also involved regional lymph nodes, and 1 involved the liver. Most cases had infiltrative margins. The tumors were generally composed of sheets of large epithelioid cells with abundant eosinophilic cytoplasm, oval to irregular nuclei, vesicular chromatin, and large nucleoli. Binucleated cells were common, and 6 cases contained tumor giant cells. Mitoses ranged from 1 to 64 per 10 HPF (median 11 per 10 HPF). Necrosis was present in 8 cases. Nearly all tumors showed a striking inflammatory infiltrate, most often of neutrophils or lymphocytes. All cases were reactive for LCA, CD45RO, and CD68 (KP1 and PG-M1); 13 of 14 (93%) expressed CD4, 12 of 14 (86%) lysozyme, 8 of 10 (80%) CD31, 7 of 14 (50%) S-100 protein, and 5 of 14 (36%) focal CD1a. Two tumors showed weak, focal cytoplasmic positivity for CD30, and 1 for epithelial membrane antigen. The tumors were negative for ALK-1, CD21, CD35, CD3, CD20, CD34, myeloperoxidase, HMB-45, and keratins. Gastrointestinal tract cases were negative for c-kit and desmin. Six patients were treated with postoperative radiation and 7 with chemotherapy (CHOP or ProMACE-MOPP). Follow-up was available for 10 patients (median, 24 months; range, 4 months to 11 years). Two tumors recurred locally, and 5 patients developed distant spread: 3 to lymph nodes, 1 to lung, and 1 to bone. At the last follow-up, 2 patients have died of disseminated disease, 4 and 5 months following initial diagnosis. The patients who died thus far had the largest primary tumors. Histiocytic sarcoma may arise primarily in soft tissue and shows reproducible histologic features, including abundant eosinophilic cytoplasm and a prominent inflammatory infiltrate. Metastatic carcinoma, metastatic melanoma, and large cell non-Hodgkin lymphomas should be excluded by immunohistochemistry. Histiocytic sarcoma has the potential for an aggressive clinical course, most often with lymph node involvement. However, a subset of cases presenting with clinically localized disease have a favorable long-term outcome. Tumor size may be a prognostic factor.

Adolescent↗